RAS protein activator-like 2 (RASAL2) initiates peritubular capillary rarefaction in hypoxic renal interstitial fibrosis

Transl Res. 2024 Mar 5:S1931-5244(24)00047-1. doi: 10.1016/j.trsl.2024.03.003. Online ahead of print.ABSTRACTThe progression of chronic kidney disease (CKD) often involves renal interstitial fibrosis (RIF) and subsequent loss of peritubular capillaries (PTCs), which enhances disease severity. Despite advancements in our understanding of fibrosis, effective interventions for reversing capillary loss remain elusive. Notably, RIF exhibits reduced capillary density, whereas renal cell carcinoma (RCC) shows robust angiogenesis under hypoxic conditions. Using RNA sequencing and bioinformatics, we identified differentially expressed genes (DEGs) in hypoxic human renal tubular epithelial cells (HK-2) and renal cancer cells (786-0). Analysis of altered Ras and PI3K/Akt pathways coupled with hub gene investigation revealed RAS protein activator-like 2 (RASAL2) as a key candidate. Subsequent in vitro and in vivo studies confirmed RASAL2's early-stage response in RIF, which reduced with fibrosis progression. RASAL2 suppression in HK-2 cells enhanced angiogenesis, as evidenced by increased proliferation, migration, and branching of human umbilical vein endothelial cells (HUVECs) co-cultured with HK-2 cells. In mice, RASAL2 knockdown improved Vascular endothelial growth factor A (VEGFA) and Proliferating cell nuclear antigen (PCNA) levels in unilateral ureteral occlusion (UUO)-induced fibrosis (compared to wild type). Hypoxia-inducible factor 1 alpha (HIF-1α) emerged as a pivotal mediator...
Source: Translational Research : the journal of laboratory and clinical medicine - Category: Laboratory Medicine Authors: Source Type: research